Alewine Garrett, Knight Jerrica, Ghantae Adithya, Mamrega Christina, Attiah Bashnona, Coover Robert A, Fahrenholtz Cale D
Department of Basic Pharmaceutical Sciences, Fred Wilson School of Pharmacy, High Point University, High Point, NC 27268, USA.
J Pers Med. 2022 Jun 30;12(7):1080. doi: 10.3390/jpm12071080.
Neurofibromatosis type 1 (NF1) is among the most common neurogenic disorders, characterized by loss of function mutations in the neurofibromin gene (). NF1 patients are extremely susceptible to developing neurofibromas, which can transform into deadly malignant peripheral nerve sheath tumors (MPNSTs). At the center of these tumors are -null Schwann cells. Here, we found that nanomedicine shows promise in the treatment of NF1-associated MPNSTs. We assessed the cytotoxicity of silver nanoparticles (AgNPs) in -null NF1-associated MPNSTs, -wildtype sporadic MPNST, and normal Schwann cells. Our data show that AgNP are selectivity cytotoxic to NF1-associated MPNSTs relative to sporadic MPNST and Schwann cells. Furthermore, we found that sensitivity to AgNPs is correlated with the expression levels of functional neurofibromin. The restoration of functional neurofibromin in NF1-associated MPNSTs reduces AgNP sensitivity, and the knockdown of neurofibromin in Schwann cells increases AgNP sensitivity. This finding is unique to AgNPs, as restoration does not alter sensitivity to standard of care chemotherapy doxorubicin in NF1-associated MPNSTs. Using an in vitro model system, we then found that AgNP can selectively eradicate NF1-associated MPNSTs in co-culture with Schwann cells at doses tolerable to normal cells. AgNP represents a novel therapy for the treatment of NF1-associated MPNSTs and addresses significant unmet clinical need.
1型神经纤维瘤病（NF1）是最常见的神经源性疾病之一，其特征是神经纤维瘤蛋白基因发生功能丧失性突变（）。NF1患者极易患上神经纤维瘤，而神经纤维瘤可转变为致命的恶性外周神经鞘瘤（MPNST）。这些肿瘤的核心是NF1基因缺失的雪旺细胞。在此，我们发现纳米药物在治疗与NF1相关的MPNST方面显示出前景。我们评估了银纳米颗粒（AgNP）对NF1基因缺失的与NF1相关的MPNST、NF1基因野生型的散发性MPNST以及正常雪旺细胞的细胞毒性。我们的数据表明，相对于散发性MPNST和雪旺细胞，AgNP对与NF1相关的MPNST具有选择性细胞毒性。此外，我们发现对AgNP的敏感性与功能性神经纤维瘤蛋白的表达水平相关。在与NF1相关的MPNST中恢复功能性神经纤维瘤蛋白可降低对AgNP的敏感性，而在雪旺细胞中敲低神经纤维瘤蛋白则会增加对AgNP的敏感性。这一发现是AgNP所特有的，因为恢复NF1基因不会改变与NF1相关的MPNST对标准护理化疗药物阿霉素的敏感性。然后，使用体外模型系统，我们发现AgNP能够在正常细胞可耐受的剂量下，与雪旺细胞共培养时选择性地根除与NF1相关的MPNST。AgNP代表了一种治疗与NF1相关的MPNST的新疗法，满足了重大的未满足临床需求。
